The present invention relates to pyridoxine and pyridoxal analogue compounds, pharmaceutical compositions containing the pyridoxine and pyridoxal analogue compounds, and methods of treatment using a therapeutically effective amount of the pyridoxine and pyridoxal analogue compounds. The pyridoxine or pyridoxal analogues can be used in the treatment of undesired platelet aggregation, cardiovascular or related diseases, and symptoms thereof.
Pyridoxal-5xe2x80x2-phosphate (PLP), an end product of vitamin B6 metabolism, plays a vital role in mammalian health. Vitamin B6 typically refers to pyridoxine, which is chemically known as 2-methyl-3-hydroxy-4,5-di(hydroxymethyl)pyridine and is represented by formula I: 
Yet two additional compounds, pyridoxal of formula II 
and pyridoxamine of formula III 
are also referred to as vitamin B6. All three compounds serve as precursors to pyridoxal-5xe2x80x2-phosphate (PLP), which is chemically known as 3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]-4-pyridine-carboxaldehyde and is represented by formula IV: 
PLP is the biologically active form of vitamin B6 inside cells and in blood plasma. Mammals cannot synthesize PLP de novo and must rely on dietary sources of the precursors pyridoxine, pyridoxal, and pyridoxamine, which are metabolized to PLP. For instance, mammals produce PLP by phosphorylating pyridoxine by action of pyridoxal kinase and then oxidizing the phosphorylated product.
PLP is a regulator of biological processes and a cofactor in more than one hundred enzymatic reactions. It has been shown to be an antagonist of a purinergic receptor, thereby affecting ATP binding; it has been implicated in modulation of platelet aggregation; it is an inhibitor of certain phosphatase enzymes; and it has been implicated in the control of gene transcription. In previous patents (U.S. Pat. No. 6,051,587 and U.S. Pat. No. 6,043,259) the role of pyridoxal-5xe2x80x2-phosphate, and its precursors pyridoxal and pyridoxine (vitamin B6), in mediating cardiovascular health and in treating cardiovascular related diseases is disclosed. PLP is also a coenzyme in certain enzyme-catalyzed processes, for example, in glycogenolysis at the glycogen phosphorylase level, in the malate asparatate shuttle involving glycolysis and glycogenolysis at the transamination level, and in homocysteine metabolism.
There is a need to identify and administer drugs that can mimic one or more of the known biological actions of vitamin B-6 congeners but that are more potent than the vitamin B-6 congeners in their specific mode of action.
The present invention provides for pyridoxine and pyridoxal analogues, pharmaceutical compositions containing the pyridoxine and pyridoxal analogues, and methods for treatment based on administration of therapeutically effective amounts of the pyridoxine and pyridoxal analogues. Compounds and compositions of the invention can be used for the treatment of cardiovascular or related diseases and symptoms thereof.
The invention provides pyridoxine and pyridoxal analogues of Formula V: 
or a pharmaceutically acceptable acid addition salt addition salt thereof, wherein:
R5 is CH2OH or CHO;
R1 is 
n is an integer of 1 to 5;
R2 , R3, and R4 are each independently
hydrogen;
alkyl;
aryl or biaryl,
wherein the aryl or biaryl can be substituted with a cyano, alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy;
amino;
acylamino;
anilino,
wherein the aniline ring can be substituted with a cyano, alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy;
nitro; or
guanidino.
In another aspect, the invention is directed to a pharmaceutical composition that includes a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula V or a pharmaceutically acceptable acid addition salt of a compound of Formula V.
In another aspect, the invention is directed to a method of treating cardiovascular or related diseases and symptoms thereof. The method includes administering to a mammal a therapeutically effective amount of a compound of Formula V or a pharmaceutically acceptable acid addition salt of a compound of Formula V in a unit dose form. The method can further include concurrent administration of another therapeutic agent.
In another aspect, the invention is directed to a method of reducing platelet aggregation and the symptoms there of a mammalian patient. The method includes administering to the mammalian patient a therapeutically effective amount of a compound of Formula V. In some instances the patient may suffer from heparin-induced thrombocytopenia (HIT).
In another aspect, the invention is directed to a method of reducing or preventing heparin-induced thrombus formation in a mammalian patient suffering from HIT. The method includes administering to the mammalian patient a therapeutically effective amount of a compound of Formula V.
In another aspect, the invention is directed to a method or reducing brain damage in a mammalian patient following embolic or hemorrhagic stroke. The method includes administering to the mammalian patient a therapeutically effective amount of a compound of Formula V.